Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".

Am J Hum Genet 2017 Nov;101(5):815-823

Centre Hospitalier Universitaire Sainte Justine Research Centre, University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylometaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of "corner fractures" at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2017.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673654PMC
November 2017
167 Reads
2 Citations
10.931 Impact Factor

Publication Analysis

Top Keywords

fn1 mutations
12
mutant proteins
8
"corner fractures"
8
individuals
5
fibronectin
5
individuals fn1
4
missense variants
4
mutations classical
4
classical sutcliffe-type
4
distinguish individuals
4
vara distinguish
4
variants pcys87phe
4
developmental coxa
4
coxa vara
4
sutcliffe-type smd
4
smd study
4
consequences fn1
4
mutations protein
4
protein level
4
level introduced
4

Similar Publications